ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming  

作　　者：Zi-jian Zhang Qi-fang Wu An-qi Ren Qian Chen Jiang-zhou Shi Jia-peng Li Xi-yu Liu Zhi-jie Zhang Yu-zhe Tang Yuan Zhao Ning-ning Yao Xiao-yu Zhang Chang-peng Liu Ge Dong Jia-xuan Zhao Mei-jun Xu Yun-qiang Yue Jia Hu Fan Sun Yu Liu Qi-lin Ao Fu-ling Zhou Hong Wu Tong-cun Zhang Hai-chuan Zhu 

机构地区：[1]Institute of Biology and Medicine,College of Life and Health Sciences,Wuhan University of Science and Technology,Wuhan,430065,China [2]School of Science,Wuhan University of Science and Technology,Wuhan,430065,China [3]Peking-Tsinghua Center for Life Sciences,and Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,100871,China [4]The MOE Key Laboratory of Cell Proliferation and Differentiation,School of Life Sciences,Peking University,Beijing,100871,China [5]Department of Medical Records,Office for DRGs(Diagnosis Related Groups),Henan Cancer Hospital,Affiliated Cancer Hospital of Zhengzhou University,Zhengzhou,450003,China [6]Key Lab of Industrial Fermentation Microbiology of the Ministry of Education&Tianjin Key Lab of Industrial Microbiology,College of Biotechnology,Tianjin University of Science and Technology,Tianjin,300457,China [7]Institute of Pathology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [8]Department of Pathology,School of Basic Medical Science,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China [9]Department of Hematology,Zhongnan Hospital of Wuhan University,Wuhan,430071,China [10]College of Life Science,Wuchang University of Technology,Wuhan,430223,China [11]Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province,College of Life Science,Wuchang University of Technology,Wuhan,430223,China

出　　处：《Acta Pharmacologica Sinica》2023年第11期2282-2295,共14页中国药理学报（英文版）

基　　金：funded by the grants from the Wuhan Science and Technology Plan Project(2019030703011533)to TCZ;China Postdoctoral Science Foundation(2021M702538);Department of Education of Hubei Province(B2021023);National Natural Science Foundation of China(82203497)to JPL;also supported by Natural Science Foundation of Hubei Province(2022CFB029);National Natural Science Foundation of China(82100193)to HCZ.

摘　　要：Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

关 键 词：T-ALL FGFR1 inhibitor AZD4547 PD-166866 drug resistance ATF4 

分 类 号：R737.14[医药卫生—肿瘤]